S-(R*,S*!N-{1-(1,3-benzodioxol-5-yl)butyl!-3,3-diethyl-2-4-(4-methyl-1-p iperazinyl)carbonyl!phenoxyl!-4-oxo-1-azetidinecarboxamide (EI) shown below: ##STR1## a selective, non-toxic, orally active human elastase inhibitor, is currently being evaluated for treatment of cystic fibrosis. Consequently, large quantities of (EI) are needed to support drug development studies.
Synthetic routes to compounds similar to (EI) have been described; see for example EP 0,481,671, which suggests (EI) could be formed by joining the substituted cyclic lactam portion of (EI) with R-.alpha.-propyl-piperonyl via a carbonyl linker. R-.alpha.-propyl-piperonyl amine, a chiral amine, could, therefore, be a significant intermediate in this process if an efficient, industrially scalable route were known.
Humphrey et al, in U.S. Pat. No. 5,149,838, discuss formation of (R)-1-(benzo.beta.!furan-5-yl)-1-aminobutane from 5-bromobenzo.beta.!furan. The process described involves as a last step the conversion of (S)-1-(benzo.beta.!furan-5-yl)-1-butanol to (R)-1-(benzoB!furan-5-yl)-1-aminobutane under Mitsonobu conditions. Unfortunately, side reactions and stereochemical leakage predominated when a Mitsunobu process was applied to the synthesis of R- or S-.alpha.-propyl-piperonyl amine, an intermediate useful for making compounds like EI.
Bringmann et al, in DE 3,819,438, describe formation of chiral amines by reacting substituted-aryl ketones with chiral methylbenzylamine, hydrogenating the resulting imine over Ra--Ni, at 1-200 bar and from 20 to 60.degree. C., and removal of the phenethyl group by hydrogenating over Pd/C at 1-200 bar and 20 to 50.degree. C. Bringmann et al, in Tetr. Lett. 1989, 30(3), 317, report reduction of chiral imines formed using S-.alpha.-methylbenzylamine by hydrogenating at 5 bar hydrogen with Ra--Ni in EtOH. Bringmann et al, in Synlett 1990, 253, report reduction of chiral imines formed using S-.alpha.-methylbenzylamine by hydrogenating at 60 bar with Pd/C or with NaBH.sub.4. In addition, Bringmann et al, in Leibigs Ann. Chem. 1990, 795, detail hydrogenolysis of N-(1-phenylethyl)-1-arylethylamines using either hydrogen and palladium on carbon for three weeks or ammonium formate and palladium on carbon. However, the present inventors have found hydrogenolysis of (R)-N-1-(1,3-Benzodioxol-5-yl)butylidene!-.alpha.-methylbenzene-methanami ne using the procedures described by Bringmann et al was either very slow or racemization of R-.alpha.-propyl-piperonyl amine occurred.
Eleveld et al, J. Org. Chem 1986, 51, 3635, report the hydrogenation of chiral imines, in particular N-(methyl(o-methoxy)benzylidene)-.alpha.-methylbenzyl amine. Hydrogenation with Pd/C and 3 atm hydrogen produced greater than 90% de of the SS isomer. In comparison, the corresponding m-methoxy imine resulted in only a 67% de. The high de obtained with the o-methoxy compound was attributed to the steric hinderance provided by the o-methoxy group. One readily realizes that R- and S-.alpha.-propyl-piperonyl amines contain only m-alkoxy groups. Thus, the procedure of Eleveld et al would not be expected to be of use in making R- and S-.alpha.-propyl-piperonyl amines.
Ukaji et al, Chem. Lett. 1991, 173, indicated the reaction of oxime ethers with allylmagnesium bromide provided little diastereoselectivity. If the oxime ether was separated into its E and Z isomers, then allylmagnesium bromide complexed with cerium chloride provided de's ranging from 50-72%. Based on this report, one would probably need cerium chloride if a Grignard reaction was used as an intermediate step in the formation of R- or S-.alpha.-propyl-piperonyl amine. However, cerium chloride is usually avoided and 50-72% de is rather low.
Wu et al, J. Org. Chem 1991, 56, 1340, report diastereoselective addition of Grignard reagents (e.g., methyl, ethyl and butyl) to 2-aryl-1,3-oxazolidines. Again, cerium trichloride was indicated as enhancing the diastereoselectivity of the Grignard addition. Addition of methylmagnesium bromide to p-methoxyphenyl-4-phenyl-1,3-oxazolidine provided high diastereoselectivity, but only a 45% yield. Such low yields aren't useful for industrial purposes.
Higashiyama et al, Chem. Pharm. Bull. 1995, 43(5), 722, discuss Grignard addition to chiral aliphatic imines derived from (R)--O-methylphenylglycinol. However, cerium trichloride is used. Removal of phenylglycinol was achieved by hydrogenating over palladium hydroxide in ethyl acetate.
Based on the above-noted articles, it would seem to be difficult to efficiently produce R- and S-.alpha.-propyl-piperonyl amines on large scale without using undesirable reagents. It is thus desirable to find a new synthetic procedure for industrial scale production of R-.alpha.-propyl-piperonyl amine and its analogs.